1. Field of the Invention
The present invention relates to 4,6-disubstituted aminopyrimidine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases and stroke. Furthermore, the present invention is directed towards pharmaceutical composition containing at least one of the 4,6-disubstituted aminopyrimidine derivatives and/or pharmaceutically acceptable salts thereof.
2. Background Art
One of the most important and fundamental processes in biology is the division of cells during the cell cycle. This process ensures the controlled production of subsequent generations of cells with defined biological function. It is a highly regulated phenomenon and responds to a diverse set of cellular signals both within the cell and from external sources. Cyclin dependent kinases (CDKs) play a key role in regulating the cell cycle machinery. These complexes consist of two components: a catalytic subunit (the kinase) and a regulatory subunit (the cyclin). To date, eleven kinase subunits have been identified (S. Mani et al., Exp. Opin. Invest. Drugs 2000, 9(8), 1849-1870, J. C. Sergere et al., Biochem. Biophys. Res. Commun. 2000, 276, 271-277, D. Hu et al, J. Biochem. Chem. 2003, 278(10), 8623-8629).
It is known, that CDKs play a role in the regulation of cellular proliferation. Therefore, CDK inhibitors could be useful in the treatment of cell proliferative disorders such as cancer, neuro-fibromatosis, psoriasis, fungal infections, endotoxic shock, transplantation rejection, vascular smooth cell proliferation associated with arteriosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis (U.S. Pat. No. 6,114,365). CDKs are also known to play a role in apoptosis. Therefore CDK inhibitors could be useful in the treatment of cancer; autoimmune diseases, for example systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes; neurodegenerative diseases for example Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases; hematological diseases, for example, chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain and for the treatment of cardiovascular diseases (U.S. Pat. No. 6,107,305 and WO 02/100401). Further it is known, that CDK inhibitors could be used for the treatment of virally induced infectious diseases, such as EBV, HBV, HCV and HIV (WO 02/100401).
Recently, it was described, that HIV-1 replication could be affected by inhibiting CDKs (C. de la Fuenta, Current HIV research, 2003, 1(2), 131-152; Y. K. Kim et al., Molecular and Cellular Biology, 2002, 22(13), 4622-4637). Especially CDK9 is reported to be essential for the HIV-1 replication (H. S. Mancebo et al, Genes Dev. 1997, 11(20): 2633-44, O. Flores et al., Proc Natl. Acad. Scd. USA. 1999, 96(13):7208-13).
Most of the known CDK inhibitors, such as olomoucine, roscovitine, CYC202, purvalanols, indolinones, paullones and 7-hydroxy-staurosporine are focusing on the inhibition of CDK1 and CDK2 with the goal of antitumor activity (Current opinion in Pharmacology, 2003, 3, 1-9). A summary of the known CDK-inhibitors is given by M. Huwe et al. (A. Huwe et al., Angew Chem Int Ed Engl. 2003; 42(19): 2122-38).
Flavopiridol is described as a low-molecular, but unselective inhibitor of CDKs, including CDK9 (W. Filgueira de Azevedo et al., Biochem. and Biophys. Res. Commun. 2002, 293(1), 566-571). Other compounds that were shown to inhibit CDKs are staurosporine, fascaplysin and hymenialdisine.
The use of 4-Aminopyrimidine derivatives as neuroprotective agents is described in WO 02/12198. These compounds generally contain as a basic residue a substituted amine in para position of the anilino part of the molecule and it is stated, that these compounds did not inhibit MEK1/2 kinase activity in P19 neurons.
U.S. Pat. No. 3,950,25 describes the use of 4-Amino-6-aryl-pyrimidines as platelet aggregation inhibitors and bronchodilators. U.S. Pat. No. 3,478,030 describes the synthesis of benzamide substituted anilino aminopyrimidine derivatives. These compounds are used as potent dilators of coronary arteries. WO 02/79197 describes the use of aryl-substituted 2-aminopyrimidine derivatives as protein kinase inhibitors, for example as inhibitor of JNK, GSK-3, Src, Lck or CDK2.
There is a high unmet medical need to develop CDK inhibitors, useful in treating various conditions associated with CDK activation, in particular concerning CDK9 kinase activity, which is associated with HIV replication.